The compounds of formula 1 are known from WO 02/32899 (corresponding to U.S. Patent Application Pub. No. 2004/0087617, which is hereby incorporated by reference). They have valuable pharmacological properties and can provide therapeutic benefit as highly effective anticholinergics in the treatment of respiratory complaints, particularly in the treatment of inflammatory and/or obstructive diseases of the respiratory tract, particularly for treating asthma or chronic obstructive pulmonary disease (COPD).
When treating the above diseases, it is convenient to administer the active substance by inhalation. In addition to the administration by inhalation of broncholytically active compounds in the form of metered aerosols and inhalable solutions, the administration of inhalable powders containing active substance is also of particular importance.
In the case of active substances with a particularly high efficacy, only small amounts of the active substance are needed per single dose to achieve the therapeutically desired effect. In such cases, the active substance has to be diluted with suitable excipients to prepare the inhalable powder. Because of the large amount of excipient, the properties of the inhalable powder are critically influenced by the choice of excipient. When choosing the excipient, its particle size is particularly important. As a rule, the finer the excipient, the poorer its flow properties. However, good flow properties are a prerequisite for highly accurate metering when packing and dividing up the individual doses of preparation, e.g., when producing capsules (inhalettes) for powder inhalation or when the patient is metering the individual dose before using a multidose inhaler. Moreover, the particle size of the excipient is very important for the emptying characteristics of capsules when used in an inhaler. It has also been found that the particle size of the excipient has a considerable influence on the proportion of active substance in the inhalable powder which is delivered for inhalation. The term inhalable proportion of active substance refers to the particles of the inhalable powder which are conveyed deep into the branches of the lungs when inhaled with a breath. The particle size required for this is between 1 μm and 10 μm, preferably less than 6 μm.
The aim of the invention is to prepare an inhalable powder containing the active substance of formula 1 which, while being accurately metered (in terms of the quantity of active substance released and delivered to the lungs on each inhalation process) with only slight variations between batches, enables the active substance to be administered in a large inhalable proportion. A further aim of the present invention is to prepare an inhalable powder containing the active substance of formula 1 which ensures good emptying characteristics of the capsules, if the powder is administered by means of powder-filled capsules.
A further aim of the invention is to provide an inhalable powder which is characterized by a high degree of homogeneity of the powder mixture and minimal fluctuations in the dispersion characteristics from one batch of powder to the next. The homogeneity of the powder mixture and minor fluctuations in the dispersion properties are crucial in ensuring that the inhalable proportion of active substance is released reproducibly in constant amounts and hence with the lowest possible variability. Accordingly, the present invention also sets out to prepare an inhalable powder which allows the inhalable proportion of active substance to be administered with the lowest possible variability.
The characteristics of emptying from the powder reservoir (the container from which the inhalable powder containing the active substance is released for inhalation) play an important part, not exclusively, but especially in the administration of inhalable powders using powder-filled capsules. If only a small amount of the powder formulation is released from the powder reservoir as a result of minimal or poor emptying characteristics, significant amounts of the inhalable powder containing the active substance are left in the powder reservoir (e.g., the capsule) and are unavailable to the patient for therapeutic use. The result of this is that the dosage of active substance in the powder mixture has to be increased so that the quantity of active substance delivered is sufficient to produce the desired therapeutic effect.
Against this background, the present invention further sets out to provide an inhalable powder which is also characterized by very good emptying characteristics.